DESCRIPTION: This is the resubmission of a new application to study intestinal defense and susceptibility in viral enteritis. The intestinal epithelium must function both as a barrier to noxious agents such as toxins and microorganisms and as a site of absorption for essential nutrients. In viral gastroenteritis, pathogenic viruses damage the barrier function of the gut with resultant failure of absorption of critical nutrients including water and salt. The central objective of this proposal is to better understand factors which determine whether enteric viruses such as astrovirus will succeed in producing infection and disease. Proteolytic enzymes in the intestinal lumen dramatically enhance astrovirus infection. The mechanism by which the astrovirus capsid protein is preteolytically processed and the nature of the enhanced infectivity will be defined in one series of experiments. Epitopes of astrovirus which elicit protective, neutralizing antibodies will be defined and mapped in vitro using monoclonal antibodies. The mechanisms by which these antibodies neutralize astrovirus will be explored. Systemic and mucosal humoral immune responses in children with astrovirus infection will be characterized and compared to the in vitro neutralizing epitope studies. Astrovirus infection of children in a pediatric hospital will be monitored by active surveillance and correlated with known and suspected risk factors for infection and disease. Viral gastroenteritis is a very important public health problem both in the developed world where diarrhea leads to thousands of hospitalizations and in the developing world where hundreds of thousands of children die from diarrheal disease. Studies such as these can lead to better understanding of intestinal barrier function and how it can be overcome. Such understanding may lead to better strategies for treatment and prevention of a variety of intestinal illnesses.